Interactions Between IGFB-3 and Retiniod X Receptors in Prostate Cancer: Over the last decade, we and others have shown that the IGF axis in general and IGFBP-3 in particular, are important determinants of prostate cancer cell growth and death and represent epidemiological risk factors for this disease. Concurrently, we have characterized the role of nuclear retinoid-related receptors in cell function including neoplasia development. These two areas of research converged last year when we discovered that RXR serves as a nuclear receptor for IGFBP-3 and that ligands for RXR may co-operate with IGFBP-3 in inducing prostate cancer cell death. We propose to investigate the role of IGFBP-3 and of RXR agonists in the regulation of androgen-dependent and androgen-independent prostate cancer. Preliminary data indicate that IGFBP- 3 and RXR ligands synergize to regulate expression of prostate target genes and to induce cell death. Thus, we will test the following hypotheses: 1) The nuclear receptor RXR mediates critical growth inhibitory pathways in prostate cancer and ligands for these receptors can amplify growth suppression and apoptosis of CaP in vivo and in vitro. 2) IGFBP-3 is a potent growth- inhibitory, apoptosis-inducing, agent that affects prostate cancer cells through an IGF-independent mechanism involving modulation of gene transcription in concert with RXR. 3) By binding RXR, IGFBP-3 modulates and participates in gene transcription events acting as a regulator of nuclear receptor function and potentially affecting recruitment of other members of the co-activator complex. 4) These interactions can be targeted for therapy of CaP. Treatment of CaP tumor-bearing SCID mice (potentially of humans with advanced prostate cancer) with combinations of RXR ligands and IGFBP-3 may result in synergistic effects on tumor suppression with reduced toxicity. Therefore, our objectives for this project are: 1) To explore IGFBP-3 and/or retinoid receptor pathways as targets for CaP therapy using in vivo animal models. 2) To understand the molecular basis of the interaction between the RXR and IGFBP-3 signaling pathways. 3) To develop a clinical trial in men with high risk localized prostate cancer using RXR ligands and IGFBP-3. If successful, our findings may validate these targets for clinical development for use in men with CaP. These therapies may be particularly useful in men with androgen independent prostate cancer, where restoration of the suppressed IGFBP-3-RXR-apoptosis pathway could prove important.